The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed computational de novo design incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW > 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, ZINC3979524, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2.
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